Developmental disorder model based on fetal hypothalamic GABA-Cl system disturbances

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19682
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Internal medicine of the bio-information integration and related fields
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: FUKUDA Atsuo 浜松医科大学, 医学部, 教授 (50254272)
• Research Collaborator: AKITA Tenpei ; WATANABE Miho ; HATA Kenichiro
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: 発達障害 / 低栄養 / 胎児脳 / ストレス / 視床下部 / 精神疾患 / KCC2 / CRH

Outline of Final Research Achievements

We confirmed that c-fos expression was elevated in AgRP cells in the arcuate nucleus and in CRH cells in the paraventricular nucleus by feeding restriction, thus established evaluation methods for both known and novel HPA axis reaction in maternal malnourished fetuses. In the maternal malnutrition model for genetically modified mice, food restriction (-30%) was performed on pregnancy at 10.5-18.5 days, establishing a fetal malnutrition mouse model, and the developmental state of AgRP cells and CRH cells were evaluated in the fetal brains. In addition, it was suggested that proper suppression of the phosphorylation of Thr906 and Thr1007 of KCC2 during the fetal stage is important for the normal neurogenesis and migration of neurons. Prenataly-stressed GAD67 heterozygous fetuses were found to show some of psychiatric disease phenotypes.

Free Research Field

神経生理学

Academic Significance and Societal Importance of the Research Achievements

精神的ストレスや低栄養ではHPA軸の活動が高まり、室傍核のCRH細胞に投射する抑制性GABA神経は細胞内Cl-濃度依存的にHPA軸活動を変化させる。胎児期の母親の低栄養や子のGABA神経系の異常は精神神経疾患のリスクとして知られるが、胎児のHPA軸機能がGABA作用変化により受ける影響はわかっていない。そこで、母体に食餌制限を行ったり、CRH細胞やAgRP細胞（GABA陽性）で遺伝子操作をして、胎仔のHPA軸反応、神経細胞の発生・移動及び生後の発現型を評価した。母体低栄養やストレスが胎仔GABAシステムを介して、HPA軸に作用して精神神経疾患様の発現型を誘導することを明らかにした。